This project deals with the design, syntheses, pharmacological evaluations, and computational studies of non-competitive antagonists on N-methyl-D-aspartate (NMDA) receptors. These transmembrane amino acid receptors are located on neurons in the central nervous system. Upon excitation of these receptors, a cation channel opens. The target compounds are expected to bind inside of and block this channel, thus preventing further firing of the neuron. Such overfiring occurs during states of ischemia and hypoglycemia when levels of the endogenous excitants l-glutamate and l-aspartate are elevated. It can result in neuronal degeneration and cell death. This is observed in stroke and is suspected to play roles in neuronal diseases such as Alzheimer's, Parkinson's, and epilepsy. Consequently, several groups are studying NMDA receptors as a therapeutic target. For this study, the lead compound is the dissociative anesthetic phencyclidine (PCP). It is known to bind to NMDA, sigma (s), and cholinergic (nicotinic) receptors, inhibits reuptake of biogenic amines (dopamine, norepinephrine, and epinephrine), and interacts with voltage-gated potassium (K+) channels. Consequently, it exhibits a lot of activities, many of which are undesirable. It also has a high abuse potential. Some structure-activity relationship studies have been conducted on PCP and its analogs. The good news are that several of those compounds have been found to exhibit less neurological toxicities than conventional NMDA antagonists and have made it to clinical trials in humans. The main problem encountered in the trials was psychosis and the compounds were not developed further for this reason. There is some literature linking activity on s receptors with psychosis though this remains controversial. Our hypothesis is that appropriately designed PCP analogs will be selective non-competitive NMDA receptor antagonists, by being more potent on those receptors and/or significantly less on alpha receptors. A corollary to this hypothesis is that a compound that is selective for NMDA receptors and which binds poorly on alpha-receptors will not have psychotic effects. The goals of this study are to synthesize three series of compounds designed to probe differences in NMDA and alpha-receptor binding sites. We also seek to continue developing a computational model to decipher any correlation between structures of the target compounds and binding affinities on NMDA receptors.